Epidemiological studies point to a relationship between the dietary intake of vitamins A and D and the incidence of breast cancer, this relationship indicates that these dietary factors may have a chemopreventive action. Animal studies confirm the preventive efficacy of vitamins A and D in breast cancer. In some instances these vitamins have been used successfully to treat overt disease but in other cases cancer cells and tumors become resistance to treatment. These data illustrate the need for investigations into two fundamental areas. Firstly, the failure of more advanced malignancies to respond to vitamin A or D therapy clearly indicates that timing and duration of exposure to these agents is of paramount importance. For example, it is possible that exposure to diets high in vitamins A and D early in life may well protect from the subsequent development of breast cancer whereas adult exposure may be less efficacious. Understanding, when, during breast development and malignancy, these vitamins are most efficacious is very important. Secondly, even though the anti-cancer actions of vitamins A and D are clearly mediated via interaction with their respective nuclear receptors it is still not clear exactly what the anti-proliferative/differentiation signals are. Studies that elucidate the precise mechanism(s) whereby vitamins A and D exert their anti-cancer effects are of great significance. For example a detailed understanding of these pathways may lead to the development of agents or dietary regimens that are effective in patients that are resistant to vitamin therapy. Recent work from the Byers' group demonstrates that the wnt/beta-catenin/TCF oncogenic pathway involved in mammary gland development and implicated in breast cancer is a key intermediary in the action of vitamins A and D. This project proposes a series of molecular studies to define this relationship more precisely and to investigate other vitamin A and D-sensitive pathways. These basic science studies are coupled to other studies in which transgenic animals are used to test the effects of vitamins A and D exposure on breast cancer development and the role of their receptors in protection from breast cancer. Finally, we will use gene microarrays and cluster analysis to identify, groups of genes that are commonly and perhaps inversely regulated by, the pathways that cause breast cancer (e.g. erbB2 or beta-catenin) and those which prevent it (e.g. vitamins A and D).